Parenteral solution of anti-hemorrhagic compounds



ussaniss Patented Aug. 1, was

SEARCH ROOM mnan'reann SOLUTION or ANTI- mznroaanacrc comrounns Gustaf Harry Carlson and Dilworth Thomas Rogers, Pearl River, N. Y., assignors to Lederle Laboratories, Inc., New York, N. Y., a corporation of Delaware No Drawing. Application January 28, 1941, Serial No. 376,328

7 Claims.

This invention relates to anti-hemorrhagic compositions and more particularly relates to parenteral solutions of anti-hemorrhagic compounds in organic esters.

A number of'anti-hcmorrhagic compounds of the vitamin K type have been found to be useful in the prevention and treatment of hypoprothrombinemia and the hemorrhagic diathesis f the newly born and in the treatment of postoperative bleeding in jaundice or persons having prothrornbin deficiencies.

In the past these substances have been administered orally or parenterally in solutions of fixed oils such as olive oil; or in some instances, water soluble salts of the compounds have been used for parenteral injection. The parenteral solutions available heretofore have not been entirely satisfactory. The oil solutions are not entirely stable to light, the rate of absorption is retarded somewhat, and frequently anatomical changes occur at the site of injection. The aqueous parenteral solutions of the salts are somewhat more desirable than the oil solutions but have the disadvantages that the salts are not always equivalent in activity to that of the parent substance and some of the anti-hemorrhagic compounds do not form wa er soluble salts which are suitable for parenteral injection.

In accordance with the present invention it has been found that certain organic esters may be used as solvents. for anti-hemorrhagic compounds and that the solutions are suitable for parenteral Suitable esters for preparing the solutions of the present invention include the ethyl and butyl esters of certain dicarboxylic acids; namely, suceinic and pimelic. These 'sters have been found to be satisfactory solvents for producing parenteral solutions of any of the water insoluble sub stances possessing vitamin K activity. These anti-hemorrhagic compounds include those such as: 2-methyl-3-phy|.yi-1,4-naphthoquin'one, 2- methyl 3 h y d r o x y lA-naphthoquinone, 2- methyl-1,4-naphthoquinone, Z-nfiethyl-lA-naphthohyrlroquinone, dimethoxynaphthalene, 2.3-dimethyi-1,4-naphthoquinone, 4- imi'no-2-methyli-naphthol, 2-methyl-l-naphthoi, and Z-methyl- 1-naphthlya-mine. The first-mentioned corn pound above is the natural vitamin K and the remainder of the compounds for the most part are vitamin K analogs. One of the simplest members of this series of antivhemorrhagic substances is 2-methyl-1,4-naphthoquinone, and it is the preferred substance for'preparing the parenteral solution of the present invention because of its outstanding anti-hemorrhagic action.

A number of tests have been carried out using solutions of this anti-hemorrhagic substance in ethyl succinate. n-butyl succinate, ethyl 'pimelaie, and n-butyl pimelate, and the solutions were found to be suitable for parenteral administration. The solutions showed no toxic effects and produced no anatomical changes at the site of injection. Absorption of the quinone from the esters was rapid and th. anti-hemorrhagic effect was at least equivalent to that of the quinone when used by other methods.

In carrying out the present invention it has been found that the esters of aliphatic alcohols having an even number of carbon atoms and the dicarboxylic acids, succinic and pimelic, produce satisfactory parenteral solutions. whereas the alcohols having an uneven number of carbon atoms such as methyl and propyl do not form esters which are suitable for parenteral administration even with succinic and pimelic acid. This would appear to indicate that certain esters produce unforeseen toxicities and that even chemically closely related. esters behave differently. Toxicity tests, however, on ethyl succinate, n-butyl succinate, ethyl p'imelate, and n-butyl pimelate show the specificity of these applicable esters. These esters may likewise be used for preparing parenteral solutions of water insoluble therapeutic compounds other than those specifically claimed in this invention.

In general, the parenteral solutions of this invention are prepared by dissolving, for example. 2- rnethyl-1,4-naphthoquinone in one of 'the esters mentioned above in such a proportion that 0.5 cc. of solution will contain about 2 mg. of the quinone. These proportions, of course, may be varied to suit the individual case and solutions may contain from 0.6 to 4mg. per each 0.5 cc. of solution or the same quantity may be con- Table 2-Three day test F-GROUP F TESTS Control Chic]; number... 101 102 103 106 108 109 110 Clotting time 30 30 8' 25" 30 30 28' 25" 17' 20" 1.5 K| m ethyl succinat Cluck number f 141 142 145 146 148. 150 Clotting time 30' 13' 50" 20' 26' 5'10" 3' 55" Table 3--Three day test SUMMARY Group Nmm Peb Pep Clotting time-minutes test Supplement Level ber cent cent I -i 0-5 e1oI111s1e-20l21-25 2e-so a0 F Control 1 14 14 1 1 1 4 K1 inethyl succm' ate 1.5 6 67 3 l 2 Table 4-Eigivte'm hour test summary I Group Su 1 I L Per Pep Clotting time-minutes w pp ement eve] cellit eent Control 6 0 0 Cuinone in oil 1 8 63 63 Guinone in ethyl pimelate l-y 8 75 88 Quinone in butyl succinate 1 8 100 100 Control 5 0 0 Quinone in oil l-y 4 25 25 guinone in ethyl succinate l 6 100 100 ontrol 6 0 0.----- Quinone in oil 1 8 25 60 O Quinone in ethyl succinate 7 57 71 C 7 71 71 6 83 100 7 57 57 6 60 83 7 86 100 10 0 0 15 13 14 21 57 ontrolnu 9 0 0 Quinone in oil l 14 60 80 Quinone in butyl succinate l-y 15 20 67 =microgram (gamma).

=less than.

=more than. Y

An examination of the results in the above tables reveal that the activity or vitamin K1 and 2-methyl-1;4-napthoquinone when administered in the organic esters of the present invention are in every instance at least the equivalent of simitions of this invention are rapidly absorbed and produce no anatomical change at the site of in-' jection.

It has beenknown in the past that in some cases of prothrombin deficiency it is desirable to administer bile salts along with the-antihemorrhagic substances and the present invention does not therefore preclude the use of bile salts and may be used in conjunction therewith. Simi-- larly the use of surface active substances, such as di-octyl sodium sulfo-succinate is not precluded.

What we claim is:

y 1. A parenteral solution comprising a water insoluble anti-hemorrhagic substance and an ester included'in the group consisting of ethyl succinate, n-butyl suc'cinate, ethyl pimelate and nbutyl pimelate.

2. A parenteral solution comprising a water insoluble anti-hemorrhagic substance in ethyl succinate. I

\3. A parenteral solution comprising a water insolubl anti-hemorrhagic substance in 'n-butyl succinate.

- 4, A parenteral solution comprising a water insoluble anti-hemorrhagic substance in ethyl pimelate. l

5. A composition suitable for parental administration comprising a solution or 2-methyl-1,4- naphthoquinone in ethyl succinate.

6; A composition suitable for parenteral administration comprising a' solution of 2-methyl-1,4- naphthoquinone in n -butyl succinate. I

7.- A composition suitable for parenteral administration comprising a solution of 2-methyl-1,4- naphthoquinone in ethyl succinate.

GUSTAF HARRY CARLSON. DILWORTH THOMAS ROGERS.

CERTIFI GATE 0F CORREU 'i'i ON Patent No. 255L758. August 1, 19th.

VGUSTAF HARRY CARLSON, ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as 011 6; Page 1, first column,- line 148, for "l-naphthlyamine" read -l-naphthy la mine--; page 5, second column, line 56, claim 5, for "parental" read -parenteral--; line 6h, claim '?,for "succinate" read -pimelate--; and that the said Letters Patent shouldbe read with this correction therein that the same may conform to the record of the case in the Patent Office,

Signed and sealed this 26th day of September, A. D. 19th,.

Leslie Frazer (Seal) Acting Commissioner of Patents. 

